We are determining how DCs differ in NOD mice compared to non-autoimmune strains, and how DCs are different in NOD mice at different diabetes pathogenesis states and disease sites. We have focused on the prediabetic phase when both pathogenic and regulatory signals are competing. We compared gene expression of sorted DC subsets from NOD and control B6 mice with and without innate stimulation, and have identified differences in the cytokine and costimulatory responses of NOD DCs. We also find that, despite higher IFN-alpha and IFN-beta production, type 1 IFN-responsive genes are induced less in NOD DCs after CpG stimulation. Canonical IFN-alpha receptor signaling is impaired after IFN-alpha stimulation in NOD DCs, including decreased nuclear localization of activated STAT1.